The researchers monitored the cognitive symptoms of 496 patients with Alzheimer’s disease in the Phase 2b/3 trial. Over 14 months, the therapy had no effect in patients with mild Alzheimer’s, but the therapy successfully slowed cognitive decline for those with moderate Alzheimer’s, which causes severe symptoms such as difficulty performing routine tasks.

Approved Alzheimer’s treatments cannot slow the disease progression, only treat the symptoms. As Grifols’ therapy is designed to address the cause of the tissue damage, it could change the face of Alzheimer’s therapeutics if approved.

“This is the most significant development in the treatment of patients with moderate Alzheimer’s disease in over 15 years,” stated Mercé Boada, director of Fundació ACE, one of the participating centers in the study. “It is also important to note that this procedure is safe and feasible.”

One hypothesis of Alzheimer’s disease suggests that the protein amyloid-beta accumulates in brain tissue and damages it. Grifols’ therapy is designed to stop this by extracting blood plasma from the patients and replacing it with a solution of albumin, a protein that amyloid-beta sticks to, clearing it from the brain and slowing the disease progression.

Many treatments based on reducing amyloid-beta levels have failed in the clinic, so much so that many pharma companies have ceased all drug development based on this strategy.

Steve’s Take:

Yes, you heard it right: Spanish drugmaker Grifols just presented positive top-line results (Phase 2b/3) from its AMBAR (Alzheimer Management by Albumin Replacement) study at the Clinical Trials on Alzheimer’s Disease (CTAD) congress on October 27, 2018 in Barcelona.

Presenting the study results, Dr. Antonio Páez, Grifols’ medical director and head of the AMBAR clinical program, confirmed that the analysis of AMBAR data in moderate patients has shown positive, highly relevant results in a cohort of patients suffering from moderate Alzheimer’s disease (AD). After the actual presentation, Grifols’ shares closed the week up 17% at €25.68 as of Monday, November 5, 2018.

The combination of plasmapheresis (a well-known and safe procedure used in plasma exchange) with Albutein 20% (albumin–a safe, well-tolerated plasma protein with multiple properties) has demonstrated a significant reduction in the progression of the disease in moderate AD patients participating in the study and may offer a new treatment track for the illness.

ThePharmaLetter reports that while Grifols believes its therapy “could have immediate application,” analysts are a bit more cautious about the results, which is hardly surprising given the huge number of failures in the Alzheimer’s space to date. Paris-based AlphaValue analysts say their caution is because these studies often have a high level of mistakes and Morgan Stanley analysts argue that the lack of statistical significance in some of the results invites caution until the more comprehensive breakdown of the results next year.

Nonetheless, results in the pre-specified cohort of moderate AD patients demonstrated a statistically-significant reduction of 61% in disease progression from baseline across both primary efficacy endpoints as measured by the Alzheimer’s Disease Assessment Scale-cognitive (ADAS-Cog) and the Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scales.

While a consistent delay in the progression of disease was observed in the treatment arms for the pre-specified mild cohort, the placebo arm presented a similar pattern, and the difference did not reach statistical significance.

The primary outcomes of the study were the changes from baseline to 14 months in the validated scales of cognition and activities of daily living, ADAS-Cog and ADCS-ADL, respectively. The pre-specified primary analysis was performed on the total study population and included the assessment of the differences from placebo in the primary outcomes of the following study arms:

1) three combinations of plasma exchange with albumin and IGIV replacement that shared the same volume of plasma removed (plasmapheresis) regardless of the arm;

2) an arm with all patients treated with plasma exchange; and

3) an arm that included all patients treated with plasma exchange analyzed by disease severity, namely, both mild AD and moderate AD.

Grifols’ chairman Victor Grifols Roura noted: “These results unlock a new era in the treatment of Alzheimer’s disease and Grifols will continue to explore the potential of plasma proteins and plasma exchange in further studies, adding: “We are very excited with the results, for the progress we have made and for what they may represent for society”.

Bottom Line:

Other European companies are also still trying different methods to treat Alzheimer’s disease. Labiotech.eu says another Spanish biotech, Oryzon Genomics SA (Barcelona), is using an epigenetics approach to protect neurons in the disease.

Oryzon has received approval from the Spanish Drug Agency to start a Phase 2a clinical trial with its Alzheimer’s drug, ORY-2001. The trial will evaluate the safety and tolerability of the drug in 90 patients with mild to moderate AD across hospitals in Spain, France and the UK. Specifically, the trial will monitor changes in memory and behavior, as well as variations in biomarkers in patients’ cerebrospinal fluid.

By targeting enzymes that regulate genes involved in Alzheimer’s, ORY-2001 provides an epigenetic approach to treating the disease. The drug specifically targets two enzymes: LSD1, which is involved in down-regulating beneficial genes, and MAOB, which breaks down neurotransmitters and is known to regulate neuronal amyloid beta levels in Alzheimer’s disease. Inhibiting these enzymes could promote neuronal growth and have neuroprotective effects. Preclinical data from animal studies show ORY-2001 restores memory loss, reduces aggressiveness and social avoidance, two traits associated with Alzheimer’s.

Elsewhere, the French biotech BrainVectis SAS hopes to reduce brain levels of cholesterol to treat the disease. Headquartered in Fontenay aux Roses, the biotech wants to apply some of the hottest technology–gene therapy–to neurodegenerative disease and in 2016 raised €1M in Series A to fund its efforts to stop the progression of Huntington’s and Alzheimer’s.

BrainVectis was spun out of the French Institute for Health and Medical Research (INSERM) after its Director of Research, Dr. Nathalie Cartier-Lacave, and her team developed a technique that effectively corrected Alzheimer’s and Huntington’s in animal models. Now that the company’s team is complete, its successful Series A will fund preclinical pharmacological tests to advance the treatments to the regulatory phase. The company expects to bring its therapy for Huntington’s to the clinic by 2019, followed by one for Alzheimer’s in 2021.

Dr. Cartier-Lacave’s strategy to halt neurodegeneration hinges on the restoration of cholesterol metabolism in the brain. A hallmark of the associated diseases is decreased expression of the enzyme, CYP46A1, which plays a key role in the process. BrainVectis’s gene therapy will theoretically release more of the enzyme into patients’ brains and thereby rescue cholesterol metabolism.

Hopefully, some of these treatments will be able to target the root causes of Alzheimer’s instead of just alleviating the symptoms.

Viewing Grifols as an investment, the company has a market cap of €15.8B and is on track for 2018 sales of €4.4B. Solid. The 52-week range for its stock price is €21.50 to €28.07.

Of the 24 analysts who cover the company, the consensus rating is “Outperform.”

The average 12-month price target is €26.80, up 4% from its current price. The spread to the highest target is +24%; the spread to the lowest is -30%.

The Bar Chart Technical Opinion is that the market for Grifols stock is in overbought territory and warns of a trend reversal. This, of course, will all change if Phase 3 results confirm these latest positive data. But we’ve all seen the innumerable failures at this exact same juncture where hopes are rightfully sky-high.

Better to wait a bit longer to buy some (or more) of this name, while the most recent data are parsed further. If you already own it, I suggest holding it. That 24% spread to the highest price target is mouth-watering, despite Barchart’s overbought conclusion.